Carfilzomib-dependent selective inhibition of the chymotrypsin-like activity of the proteasome leads to antitumor activity in Waldenstrom's Macroglobulinemia.

Abstract

PURPOSE:

Primary Waldenstrom's Macroglobulinemia (WM) cells present with a significantly higher level of the immunoproteasome compared with the constitutive proteasome. It has been demonstrated that selective inhibition of the chymotrypsin-like (CT-L) activity of constitutive-(c20S) and immuno-(i20S) proteasome represents a valid strategy to induce antineoplastic effect in hematologic tumors. We therefore evaluated carfilzomib, a potent selective, irreversible inhibitor of the CT-L activity of the i20S and c20S in WM cells.

EXPERIMENTAL DESIGN:

We tested the effect of carfilzomib on survival and proliferation of primary WM cells, as well as of other IgM-secreting lymphoma cell lines. Carfilzomib-dependent mechanisms of induced apoptosis in WM cells, and its effect on WM cells in the context of bone marrow (BM) microenvironment have been also evaluated. Moreover, the combinatory effect of carfilzomib and bortezomib has been investigated. In vivo studies have been performed.

RESULTS:

We demonstrated that carfilzomib targeted the CT-L activity of both i20S and c20S, which led to the induction of toxicity in primary WM cells, as well as in other IgM-secreting lymphoma cells. Importantly, carfilzomib targeted WM cells even in the context of BM milieu. In addition, carfilzomib induced apoptosis through c-jun-N-terminal-kinase activation, caspase cleavage, and initiation of unfolded protein response. Importantly, the combination of carfilzomib and bortezomib synergistically inhibited CT-L activity, as well as caspase-, PARP-cleavage and GRP94 expression. Antitumor activity of carfilzomib has been validated in vivo.

CONCLUSIONS:

These findings suggest that targeting i20S and c20S CT-L activity by carfilzomib represents a valid antitumor strategy in WM and other IgM-secreting lymphomas.

• Authors: Antonio Sacco, Monette Aujay, Brittany Morgan, Abdel Kareem Azab, Patricia Maiso, Yang Liu, Yong Zhang, Feda Azab, Hai T Ngo, Ghayas C Issa, Phong Quang, Aldo M Roccaro, Irene M Ghobrial
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 17 Issue 7 Pg. 1753-64 (Apr 01 2011) ISSN: 1557-3265 [Electronic] United States
• PMID: 21355079 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Boronic Acids
• Chemokine CXCL12
• Oligopeptides
• Proteasome Inhibitors
• Pyrazines
• Serine Proteinase Inhibitors
• Bortezomib
• carfilzomib
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases
• JNK Mitogen-Activated Protein Kinases
• Chymotrypsin
• Caspases

Topics

• Animals
• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Bone Marrow Cells (cytology, physiology)
• Boronic Acids (pharmacology)
• Bortezomib
• Caspases (metabolism)
• Cell Adhesion (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Survival (drug effects)
• Chemokine CXCL12 (pharmacology)
• Chymotrypsin (antagonists & inhibitors)
• Coculture Techniques
• DNA Fragmentation
• Drug Synergism
• Enzyme Activation
• Female
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Lymphoma (pathology)
• Mice
• Mice, SCID
• Oligopeptides (pharmacology)
• Poly (ADP-Ribose) Polymerase-1
• Poly(ADP-ribose) Polymerases (metabolism)
• Proteasome Inhibitors
• Pyrazines (pharmacology)
• Serine Proteinase Inhibitors (pharmacology)
• Unfolded Protein Response
• Waldenstrom Macroglobulinemia (drug therapy, enzymology, pathology)